Central Theme: to understand the molecular basis of specific transcriptional factor and peptide growth factor signaling mechanisms that instruct lung morphogenesis, then to understand their role in the perturbation of lung morphogenesis by injury and repair, and then to use this information to devise and evaluate novel rational therapeutic approaches. Project 1. Positive and negative regulators of lung development: will determine the role of the Nkx 2.1 family of transcriptional factors as key temporo-spatial developmental cues for normal lung morphogenesis, and will determine how Nkx 2.1 is positively and negatively regulated by peptide growth factor signaling. Project 2. TGF-beta signaling in lung morphogenesis, injury and repair: will further determine the role of endogenous TGF-beta peptide growth factor signaling in lung morphogenesis, and of excessive TGF-beta peptide expression and signaling in lung injury and repair, including its role in regulating epithelial apoptosis. Project 3. TGF-beta signaling and apoptosis: will determine the specific molecular signal transduction mechanism by which TGF-beta mediates activation of apoptosis and will relate these findings to lung injury and repair. Project 4. TGR-beta3 in lung morphogenesis, injury and repair: will further determine the specific functional roles of TGF-beta3 peptides in lung development, injury and repair/healing using novel regulatable transgenic/null mutant strategies. Project 5. TGR-beta rational therapeutics: will devise and test novel rationally based approaches to perturbing TGF-beta ligand-receptor interactions, based on functional predictions from computer modeling of ligand-receptor interactions and establish their utility in modulating excess TGF-beta signaling in lung injury and repair.